SummaryDeregulation of signal transduction is a feature of tumor cells and signaling therapies are gaining importance in the growing arsenal against cancer. However, their full potential can only be achieved once we overcome the limited knowledge on how signaling networks are wired in cancer cells. Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a ‘holistic’ view of the IL7/IL7R signaling landscape. To do so, we will employ a multidisciplinary strategy, in which data from complementary high throughput analyses, informing on different levels of regulation of the IL7/IL7R signaling network, will be integrated via a systems biology approach, and complemented by cell and molecular biology experimentation and state-of-the-art in vivo models. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7/IL7R signaling promotes leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL. Moreover, the scope of insights gained should extend beyond leukemia. Our in-depth, systems-level characterization of IL7/IL7R signaling will constitute a platform with extraordinary potential to illuminate the molecular role of the IL7/IL7R axis in other cancers (e.g. breast and lung) and pathological settings where IL7 has been implicated, such as HIV infection, multiple sclerosis and rheumatoid arthritis.

Deregulation of signal transduction is a feature of tumor cells and signaling therapies are gaining importance in the growing arsenal against cancer. However, their full potential can only be achieved once we overcome the limited knowledge on how signaling networks are wired in cancer cells. Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a ‘holistic’ view of the IL7/IL7R signaling landscape. To do so, we will employ a multidisciplinary strategy, in which data from complementary high throughput analyses, informing on different levels of regulation of the IL7/IL7R signaling network, will be integrated via a systems biology approach, and complemented by cell and molecular biology experimentation and state-of-the-art in vivo models. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7/IL7R signaling promotes leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL. Moreover, the scope of insights gained should extend beyond leukemia. Our in-depth, systems-level characterization of IL7/IL7R signaling will constitute a platform with extraordinary potential to illuminate the molecular role of the IL7/IL7R axis in other cancers (e.g. breast and lung) and pathological settings where IL7 has been implicated, such as HIV infection, multiple sclerosis and rheumatoid arthritis.

SummarySevere sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options outside of infection control and organ support measures. Based on our recent discovery that anthracycline drugs prevent organ failure without affecting the bacterial burden in a model of severe sepsis, we propose that strategies aimed at target organ protection have extraordinary potential for the treatment of sepsis and possibly for other inflammation-driven conditions. However, the mechanisms of organ protection and disease tolerance are either unknown or poorly characterized.
The central goal of the current proposal is to identify and characterize novel cytoprotective mechanisms, with a focus on DNA damage response dependent protection activated by anthracyclines as a window into stress-induced genetic programs conferring disease tolerance. To that end, we will carry out a combination of candidate and unbiased approaches for the in vivo identification of ATM-dependent and independent mechanisms of tissue protection. We will validate the leading candidates through adenovirus-mediated delivery of constructs for overexpression (gain-of-function) or shRNA for gene silencing (loss-of-function) to the lung, based on our recent finding that rescuing this organ is essential and perhaps sufficient in anthracycline-induced protection against severe sepsis. The candidates showing the most promise will be characterized using a combination of in vitro and in vivo genetic, biochemical, cell biological and physiological methods.
The results arising from the current proposal are likely not only to inspire the design of transformative therapies for sepsis but also to open a completely new field of opportunity to molecularly understand core surveillance mechanisms of basic cellular processes with a critical role in the homeostasis of organ function and whose activation can ultimately promote quality of life during aging and increase lifespan.

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options outside of infection control and organ support measures. Based on our recent discovery that anthracycline drugs prevent organ failure without affecting the bacterial burden in a model of severe sepsis, we propose that strategies aimed at target organ protection have extraordinary potential for the treatment of sepsis and possibly for other inflammation-driven conditions. However, the mechanisms of organ protection and disease tolerance are either unknown or poorly characterized.
The central goal of the current proposal is to identify and characterize novel cytoprotective mechanisms, with a focus on DNA damage response dependent protection activated by anthracyclines as a window into stress-induced genetic programs conferring disease tolerance. To that end, we will carry out a combination of candidate and unbiased approaches for the in vivo identification of ATM-dependent and independent mechanisms of tissue protection. We will validate the leading candidates through adenovirus-mediated delivery of constructs for overexpression (gain-of-function) or shRNA for gene silencing (loss-of-function) to the lung, based on our recent finding that rescuing this organ is essential and perhaps sufficient in anthracycline-induced protection against severe sepsis. The candidates showing the most promise will be characterized using a combination of in vitro and in vivo genetic, biochemical, cell biological and physiological methods.
The results arising from the current proposal are likely not only to inspire the design of transformative therapies for sepsis but also to open a completely new field of opportunity to molecularly understand core surveillance mechanisms of basic cellular processes with a critical role in the homeostasis of organ function and whose activation can ultimately promote quality of life during aging and increase lifespan.

Max ERC Funding

1 985 375 €

Duration

Start date: 2015-10-01, End date: 2020-09-30

Project acronymMEMOIRS

ProjectChildren of Empires and European Postmemories

Researcher (PI)Maria Margarida DE SA CALAFATE RIBEIRO

Host Institution (HI)CENTRO DE ESTUDOS SOCIAIS

Call DetailsConsolidator Grant (CoG), SH5, ERC-2014-CoG

SummaryMEMOIRS focuses on the intergenerational memories of the children and grandchildren of those involved in the decolonization processes of colonies held by France, Portugal and Belgium. Through interviews of this second and third generation, and a comparative analysis of the cultures influenced by the postmemory of the colonial wars and the end of empire, Europe's postcolonial heritage will be reinterrogated, and a new understanding of the contemporary continent will be developed. At the heart of the project is a desire to comprehend the effects of Europe's postimperial diversity through postmemories of colonial praxis.
The project is interdisciplinary, bringing together specialists from literary and cultural studies, history, sociology and migration studies. MEMOIRS aims to maximize the impact of its findings through broad web, open-access publications and an itinerant artistic exhibit that captures multiple aspects of the representations of postmemory, and fosters a meaningful North-South dialogue.

MEMOIRS focuses on the intergenerational memories of the children and grandchildren of those involved in the decolonization processes of colonies held by France, Portugal and Belgium. Through interviews of this second and third generation, and a comparative analysis of the cultures influenced by the postmemory of the colonial wars and the end of empire, Europe's postcolonial heritage will be reinterrogated, and a new understanding of the contemporary continent will be developed. At the heart of the project is a desire to comprehend the effects of Europe's postimperial diversity through postmemories of colonial praxis.
The project is interdisciplinary, bringing together specialists from literary and cultural studies, history, sociology and migration studies. MEMOIRS aims to maximize the impact of its findings through broad web, open-access publications and an itinerant artistic exhibit that captures multiple aspects of the representations of postmemory, and fosters a meaningful North-South dialogue.